scholarly journals Impact of somatic and germline mutations on the outcome of systemic mastocytosis

2018 ◽  
Vol 2 (21) ◽  
pp. 2814-2828 ◽  
Author(s):  
Javier I. Muñoz-González ◽  
María Jara-Acevedo ◽  
Iván Alvarez-Twose ◽  
Jason D. Merker ◽  
Cristina Teodosio ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Bone Marrow Cells ◽  
Systemic Mastocytosis ◽  
Progression Free Survival ◽  
Serum Levels ◽  
Skin Lesions ◽  
Common Mutation ◽  
Germline Variants ◽  
Targeted Next Generation Sequencing ◽  
Kit D816v

Abstract Systemic mastocytosis (SM) is a highly heterogeneous disease with indolent and aggressive forms, with the mechanisms leading to malignant transformation still remaining to be elucidated. Here, we investigated the presence and frequency of genetic variants in 34 SM patients with multilineal KIT D816V mutations. Initial screening was performed by targeted sequencing of 410 genes in DNA extracted from purified bone marrow cells and hair from 12 patients with nonadvanced SM and 8 patients with advanced SM, followed by whole-genome sequencing (WGS) in 4 cases. Somatic mutations were further investigated in another 14 patients with advanced SM. Despite the fact that no common mutation other than KIT D816V was found in WGS analyses, targeted next-generation sequencing identified 67 nonsynonymous genetic variants involving 39 genes. Half of the mutations were somatic (mostly multilineal), whereas the other half were germline variants. The presence of ≥1 multilineal somatic mutation involving genes other than KIT D816V, ≥3 germline variants, and ≥1 multilineal mutation in the SRSF2, ASXL1, RUNX1, and/or EZH2 genes (S/A/R/E genes), in addition to skin lesions, splenomegaly, thrombocytopenia, low hemoglobin levels, and increased alkaline phosphatase and β2-microglobulin serum levels, were associated with a poorer patient outcome. However, the presence of ≥1 multilineal mutation, particularly involving S/A/R/E genes, was the only independent predictor for progression-free survival and overall survival in our cohort.

Systemic Mastocytosis with c-KITD816V Mutation Treated with Dasatinib.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4656-4656 ◽  
Author(s):  
Rudolf Benz ◽  
Juerg Boesiger ◽  
Jorg Fehr
Keyword(s):  
Mast Cell ◽  
Systemic Mastocytosis ◽  
Lumbar Pain ◽  
Common Mutation ◽  
Medical Council ◽  
Imatinib Resistance ◽  
Kit Mutation ◽  
Tyrosinkinase Inhibitor ◽  
Kit D816v

Abstract Objectives: Systemic mastocytosis (SM) is mainly a clonal disease with a variable clinical outcome. Prognosis is very much related to additional symptoms. If so called c-findings are present, survival is often limited to months. Until recently only Interferon and Cladribine could show some effect on the disease progression. With the introduction of Imatinib some hope grew to treat the disease by acting on c-KIT (CD 117; stem cell factor receptor). However, the substitution of valine for aspartic acid at position 816 in c-KIT (D816V) leads to prolonged mast cell survival and increased proliferation because of constitutive activation of the tyrosine kinase of c-KIT. Between 31% and 100% of patients with SM harbour the c-KIT D816V mutation which is invariably related to Imatinib resistance. Fortunately, the new tyrosinkinase inhibitor Dasatinib (BMS-354825) could show a much higher inhibition of the c-KIT D816V mutated receptor in vitro. Therefore we treated a patient with systemic mastocytosis with associated hematologic clonal non mast cell lineage disease (SM-AHNMD) and c-findings with Dasatinib. Case description: A 69 year old patient was diagnosed 5 years ago with cutaneous mastocytosis. Because of a markedly increased tryptase levels of 130μg/l he was referred to our clinic for further investigation. In a bone marrow biopsy, the classical signs of SM could be found together with a chronic myelomonocytic leukemia (CMML) without any cytogenetic alterations. During 2 years the patient remained clinically stable without any treatment. Subsequently the patient droped weight and got strong lumbar pain. A MRI scan revealed fractures of L2 and L4 without signs for osteoporosis. Additionally, splenomegaly and hepatomegaly have been noticed with enlarged lymph nodes in the retroperitoneal space together with profound thrombocytopenia. Even SM-AHNMD is by definition of the ‘year 2000 Working Conference on Mastocytosis’ a distinct entity, the occurring c-findings together with a rapid increase in tryptase levels have been associated with an aggressive disease course. A c-KIT mutation analysis showed a D816V mutation. We decided after approval from the medical council to start the patient on Dasatinib. We started with 50mg daily for 3 days. Because no signs of acute mastcell degranulation we increased the dose to 50mg BID and continued the treatment for 13 weeks. Due to non-hematologic toxicity (fatigue) Dasatinib had to be stopped. Hepatosplenomegaly remained stable, lumbar pain disappeared even after cessation of analgetic therapy and weight increased gradually. However, laboratory follow up (tryptase, soluble interleukin 2 receptor) showed inconsistent results. Conclusion: Our patient with SM-CMML had many signs of systemic aggressive mastocytosis which is a mostly fatal variant of SM. With the introduction of Imatinib, a potent c-kit inhibitor, a novel approach to inhibit mastcell-proliferation was described. However, the most common mutation in CD117 of mastcells (D816V mutation) turned out to be resistant to Imatinib. However, Dasatinib a recently introduced tyrosinkinase inhibitor showed significant efficacy in vitro. A phase II study of Dasatinib in patients with Philadelphia-negative myeloproliferative disorders, including SM has recently been presented by Verstovsek and colleagues showing an overall response rate of 42% in SM. However, these patients were c-KIT mutation negative. This case report shows first evidence of clinical activity of Dasatinib in a patient with systemic aggressive mastocytosis harbouring the c-KIT mutation D816V. Further clinical studies in this patient population are warranted.

scholarly journals Frequency and prognostic impact of KIT and other genetic variants in indolent systemic mastocytosis

Blood ◽  
2019 ◽  
Vol 134 (5) ◽  
pp. 456-468 ◽  
Author(s):  
Javier I. Muñoz-González ◽  
Iván Álvarez-Twose ◽  
María Jara-Acevedo ◽  
Ana Henriques ◽  
Esther Viñas ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Systemic Mastocytosis ◽  
Progression Free Survival ◽  
Scoring Systems ◽  
Prognostic Impact ◽  
Limited Information ◽  
Free Survival ◽  
Pathogenic Variants ◽  
Indolent Systemic Mastocytosis

Abstract Indolent systemic mastocytosis (ISM) patients have a normal life expectancy, except in the 5% to 10% of cases that progress to more advanced SM (advSM), which has a significantly poorer outcome. Mutations in genes other than KIT frequently found in myeloid neoplasms have been associated with a poorer outcome among advSM, whereas limited information exists about their frequency and prognostic impact in ISM. We investigated the frequency and prognostic impact of variants in 18 genes, found to be altered in advSM, in 322 ISM patients (median follow-up, 5.7 years) divided into discovery (n = 200) and validation (n = 122) cohorts. Overall, 71 genetic variants were detected in 55 of 322 (17%) patients. Mutated ISM cases, particularly those carrying ASXL1, RUNX1, and/or DNMT3A (A/R/D) pathogenic variant allele frequencies (VAFs) ≥ 30%, exhibited significantly shortened (P < .001) progression-free survival (PFS) and overall survival (OS). Multivariate analysis showed that serum β2-microglobulin (sβ2M) levels > 2.5 µg/mL (hazard ratio [HR], 9.8; P = .001), together with a KIT D816V VAF ≥ 1% in bone marrow (BM) (HR, 10.1; P = .02) and pathogenic variants of A/R/D VAFs ≥ 30% (HR, 4.2; P = .02), were the best combination of independent predictors for PFS. In turn, A/R/D gene pathogenic VAF ≥ 30% was the only independent predictor for OS (HR, 51.8; P < .001). Based on these variables, 2 scoring systems were constructed for risk stratification of ISM at diagnosis with significantly different 10-year PFS (100%, 91%, 0% for scores of 0, 1, ≥2, respectively) and OS (100% and 50% for scores of 0 and 1) rates.

scholarly journals CCL2 is a KIT D816V–dependent modulator of the bone marrow microenvironment in systemic mastocytosis

Blood ◽  
2017 ◽  
Vol 129 (3) ◽  
pp. 371-382 ◽  
Author(s):  
Georg Greiner ◽  
Nadine Witzeneder ◽  
Angelika Berger ◽  
Klaus Schmetterer ◽  
Gregor Eisenwort ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Advanced Disease ◽  
Systemic Mastocytosis ◽  
Serum Levels ◽  
Bone Marrow Microenvironment ◽  
Poor Survival ◽  
Key Points ◽  
Kit D816v

Key Points CCL2 is a KIT D816V–induced cytokine targeting microenvironmental cells in mastocytosis in vitro and in vivo. Serum levels of CCL2 in patients with mastocytosis correlate with advanced disease and poor survival.

scholarly journals 5-azacytidine and decitabine exert proapoptotic effects on neoplastic mast cells: role of FAS-demethylation and FAS re-expression, and synergism with FAS-ligand

Blood ◽  
2012 ◽  
Vol 119 (18) ◽  
pp. 4242-4252 ◽  
Author(s):  
Viviane Ghanim ◽  
Harald Herrmann ◽  
Gerwin Heller ◽  
Barbara Peter ◽  
Emir Hadzijusufovic ◽  
...  
Keyword(s):  
Mast Cells ◽  
Fas Ligand ◽  
Bone Marrow Cells ◽  
Systemic Mastocytosis ◽  
M Cell ◽  
Drug Induced ◽  
Demethylating Agents ◽  
Induced Apoptosis ◽  
Kit D816v

Abstract Aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL) are advanced hematopoietic neoplasms with poor prognosis. In these patients, neoplastic mast cells (MCs) are resistant against various drugs. We examined the effects of 2 demethylating agents, 5-azacytidine and decitabine on growth and survival of neoplastic MCs and the MC line HMC-1. Two HMC-1 subclones were used, HMC-1.1 lacking KIT D816V and HMC-1.2 exhibiting KIT D816V. Both agents induced apoptosis in HMC-1.1 and HMC-1.2 cells. Decitabine, but not 5-azacytidine, also produced a G2/M cell-cycle arrest in HMC-1 cells. Drug-induced apoptosis was accompanied by cleavage of caspase-8 and caspase-3 as well as FAS-demethylation and FAS–re-expression in neoplastic MCs. Furthermore, both demethylating agents were found to synergize with the FAS-ligand in inducing apoptosis in neoplastic MCs. Correspondingly, siRNA against FAS was found to block drug-induced expression of FAS and drug-induced apoptosis in HMC-1 cells. Neither 5-azacytidine nor decitabine induced substantial apoptosis or growth arrest in normal MCs or normal bone marrow cells. Together, 5-azacytidine and decitabine exert growth-inhibitory and proapoptotic effects in neoplastic MCs. These effects are mediated through “FAS–re-expression” and are augmented by the FAS-ligand. Whether epigenetic drugs produce antineoplastic effects in vivo in patients with ASM and MCL remains to be determined.

scholarly journals PEDIATRIC MASTOCYTOSIS: AN UPDATE

2021 ◽  
Vol 13 (1) ◽  
pp. e2021069
Author(s):  
Fiorina Giona
Keyword(s):  
Systemic Mastocytosis ◽  
Histamine Receptor ◽  
Skin Lesions ◽  
On Demand ◽  
Receptor Blockers ◽  
Cutaneous Mastocytosis ◽  
Excessive Proliferation ◽  
Kit D816v ◽  
Over Time

Mastocytosis is a rare clonal disorder, characterized by excessive proliferation and accumulation of mast cells (MC) in various organs and tissues. Cutaneous mastocytosis (CM), the most common form in children, is defined when MC infiltration is limited to the skin. Systemic mastocytosis (SM), the most common form in adults, is characterized by MC proliferation and accumulation in organs, such as bone marrow, lymph nodes, liver and spleen (1). Genetic aberrations, mainly the KIT D816V mutation, play a crucial role in the pathogenesis of mastocytosis, resulting in enhancing MC survival and subsequent accumulation in organs and tissues (2,3). CM includes 3 forms: solitary mastocytoma, maculopapular cutaneous mastocytosis (MPCM) and diffuse cutaneous mastocytosis (DCM). In the majority of children with CM, skin lesions regress spontaneously around puberty; unfortunately, in a few cases, it is not a self-limiting disease (4). Even if SM occurs occasionally, all children with mastocytosis require planned follow-up over time. Children with mastocytosis often suffer from MC mediator-related symptoms, the most common of which is itching, often triggered by rubbing the lesions. Management of pediatric mastocytosis is mainly based on strict avoidance of triggers. Treatment with H1 and H2 histamine receptor blockers on demand, and the availability of epinephrine auto-injectors for the patients to use in case of severe anaphylactic reactions are recommended.

5-Azacytidine and Decitabine Induce FAS Re-Expression, Exert Major Proapoptotic Effects, and Cooperate with the FAS Ligand in Producing Apoptosis in Neoplastic Human Mast Cells,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3457-3457
Author(s):  
Viviane Ghanim ◽  
Harald Herrmann ◽  
Emir Hadzijusufovic ◽  
Barbara Peter ◽  
Katharina Blatt ◽  
...  
Keyword(s):  
Mast Cells ◽  
Fas Ligand ◽  
Bone Marrow Cells ◽  
Systemic Mastocytosis ◽  
Dependent Manner ◽  
M Cell ◽  
Drug Induced ◽  
Demethylating Agents ◽  
Induced Apoptosis ◽  
Kit D816v

Abstract Abstract 3457 Aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL) are advanced myeloid neoplasms with a poor prognosis. In these patients, neoplastic mast cells (MC) are resistant against most conventional drugs. Demethylating agents reportedly exert beneficial effects in several advanced myelogenous neoplasms, including myelodysplastic syndromes. We examined the effects of two demethylating agents, 5-Azacytidine and 5-Aza-2`Deoxycytidine (Decitabine) on growth and survival (apoptosis) of neoplastic MC and the human MC line HMC-1. Two HMC-1 subclones were used, HMC-1.1 lacking KIT D816V and HMC-1.2 exhibiting KIT D816V. Both demethylating agents were found to induce apoptosis and growth inhibition in HMC-1.1 cells and HMC-1.2 cells in a dose-dependent manner (IC50: 5-Azacytidine: 5–10 μM, Decitabine: 1–5 μM). Interestingly, only Decitabine but not 5-Azacytidine induced a major G2/M cell cycle arrest in HMC-1 cells. Drug-induced apoptosis in HMC-1 cells was accompanied by cleavage and activation of Caspase-8 and Caspase-3 as well as an increased expression of proapoptotic FAS/CD95, whereas no major effects on expression of other surface antigens were seen. We also found that both demethylating agents synergize with the FAS-ligand in inducing apoptosis in neoplastic MC. Methylation-specific PCR and bisulfite genomic sequencing revealed that the FAS-promoter is hypermethylated in HMC-1 cells. In addition, qPCR demonstrated that exposure to 5-Azacytidine or Decitabine leads to re-expression of FAS in neoplastic MC, which was confirmed by flow cytometry. Correspondingly, a FAS-specific siRNA was found to block drug-induced expression of FAS and drug-induced apoptosis in HMC-1 cells. Although other key regulators and tumor suppressor molecules such as p16 were also found to be hypermethylated in HMC-1 cells, no major demethylating effects of 5-Azacytidine or Decitabine were seen. Neither 5-Azacytidine nor Decitabine induced substantial apoptosis or growth arrest in normal human cord blood progenitor-derived MC or in control bone marrow cells. Together, our data show that 5-Azacytidine and Decitabine exert growth-inhibitory and pro-apoptotic effects in neoplastic MC. These effects are mediated through FAS re-expression and are augmented by the FAS ligand. Whether epigenetic drugs produce anti-neoplastic effects in vivo in patients with advanced SM including MCL, remains to be determined in clinical trials. Disclosures: Valent: Novartis: Consultancy, Honoraria, Research Funding.

scholarly journals Integrative Genomic Analyses of Patient-Matched Intracranial and Extracranial Metastases Reveal a Novel Brain-Specific Landscape of Genetic Variants in Driver Genes of Malignant Melanoma

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 731
Author(s):  
Renáta Váraljai ◽  
Susanne Horn ◽  
Antje Sucker ◽  
Daniela Piercianek ◽  
Verena Schmitt ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Genetic Variants ◽  
Genetic Alterations ◽  
Metastasis Formation ◽  
Driver Genes ◽  
Targeted Next Generation Sequencing ◽  
Paired Samples ◽  
Melanoma Metastases ◽  
Frequent Event ◽  
Genetic Landscape

Background: Development of brain metastases in advanced melanoma patients is a frequent event that limits patients’ quality of life and survival. Despite recent insights into melanoma genetics, systematic analyses of genetic alterations in melanoma brain metastasis formation are lacking. Moreover, whether brain metastases harbor distinct genetic alterations beyond those observed at different anatomic sites of the same patient remains unknown. Experimental Design and Results: In our study, 54 intracranial and 18 corresponding extracranial melanoma metastases were analyzed for mutations using targeted next generation sequencing of 29 recurrently mutated driver genes in melanoma. In 11 of 16 paired samples, we detected nucleotide modifications in brain metastases that were absent in matched metastases at extracranial sites. Moreover, we identified novel genetic variants in ARID1A, ARID2, SMARCA4 and BAP1, genes that have not been linked to brain metastases before; albeit most frequent mutations were found in ARID1A, ARID2 and BRAF. Conclusion: Our data provide new insights into the genetic landscape of intracranial melanoma metastases supporting a branched evolution model of metastasis formation.

scholarly journals Prognostic role of docetaxel-induced suppression of free testosterone serum levels in metastatic prostate cancer patients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Paula Kappler ◽  
Michael A. Morgan ◽  
Philipp Ivanyi ◽  
Stefan J. Brunotte ◽  
Arnold Ganser ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Metastatic Prostate Cancer ◽  
Cox Regression ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Serum Levels ◽  
Biologically Active ◽  
Free Form ◽  
Total Testosterone ◽  
The Impact

AbstractTo date, only few data concerning the biologically active, free form of testosterone (FT) are available in metastatic prostate cancer (mPC) and the impact of FT on disease, therapy and outcome is largely unknown. We retrospectively studied the effect of docetaxel on FT and total testosterone (TT) serum levels in 67 mPC patients monitored between April 2008 and November 2020. FT and TT levels were measured before and weekly during therapy. The primary endpoint was overall survival (OS). Secondary endpoints were prostate-specific antigen response and radiographic response (PSAR, RR), progression-free survival (PFS), FT/TT levels and safety. Median FT and TT serum levels were completely suppressed to below the detection limit during docetaxel treatment (FT: from 0.32 to < 0.18 pg/mL and TT: from 0.12 to < 0.05 ng/mL, respectively). Multivariate Cox regression analyses identified requirement of non-narcotics, PSAR, complete FT suppression and FT nadir values < 0.18 pg/mL as independent parameters for PFS. Prior androgen-receptor targeted therapy (ART), soft tissue metastasis and complete FT suppression were independent prognostic factors for OS. FT was not predictive for treatment outcome in mPC patients with a history of ART.

scholarly journals Identification of the Response-Related Biomarker of Bimonthly Hepatic Arterial Infusion Chemotherapy

2021 ◽  
Vol 10 (4) ◽  
pp. 629
Author(s):  
Kei Moriya ◽  
Tadashi Namisaki ◽  
Hiroaki Takaya ◽  
Kosuke Kaji ◽  
Hideto Kawaratani ◽  
...  
Keyword(s):  
Hepatic Arterial Infusion ◽  
Progression Free Survival ◽  
Serum Levels ◽  
Hepatic Arterial Infusion Chemotherapy ◽  
Advanced Hepatocellular Carcinoma ◽  
Arterial Infusion ◽  
Term Survival ◽  
Arterial Infusion Chemotherapy ◽  
Infusion Chemotherapy ◽  
Molecularly Targeted Agents

Despite the availability of molecularly targeted agents for advanced hepatocellular carcinoma (aHCC), these are limited to compensated cirrhotic patients, and concerns about decreased hepatic functional reserve (HFR) and unknown adverse events, which may affect long-term survival, remain unaddressed. In this study, we enrolled 96 aHCC patients treated with bimonthly hepatic arterial infusion chemotherapy (B-HAIC) with cisplatin or sorafenib monotherapy (oral sorafenib 400 mg twice daily) not only to demonstrate its efficacy and significance but also to indicate preferable candidates by setting a response-related biomarker. Differences in treatment had no significant effect on overall survival (OS). The response rate in patients treated with B-HAIC was relatively higher than those treated with sorafenib. HFR was well maintained over the treatment course with B-HAIC, while it was significantly impaired with sorafenib. By employing multivariate analysis, we found negative trends between progression-free survival (PFS) periods and serum levels of alpha fetoprotein as well as des-gamma-carboxy prothrombin (DCP). In addition, a logistic regression analysis of the relationship between serum DCP levels and PFS periods over 420 days (14 months) showed that the PFS periods of patients with higher DCP was significantly shorter than those of patients with lower DCP (p = 0.02). Subsequently, the present study demonstrated the efficacy and safety of B-HAIC and identified a predictor of unpreferable patients. Based on these results, B-HAIC might be an alternative treatment after the implementation of new molecularly targeted therapies.

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